tbuckley/cabot-search huggingface dataset:
Abstract 5357: mTOR kinase inhibitor AZD8055 reverses acquired rapamycin resistance in prostate cancer cells
Authors: Yao Dai, Dietmar Siemann
Journal: Cancer Research (2022)

Abstract The mTOR pathway is frequently over-activated in human cancers. However, classic allosteric mTOR inhibitors rapamycin only exerts limited clinical benefits. It has been shown that prostate cancer are able to acquire resistance after rapamycin treatment for a period of time. Such secondary resistance remains as major concerns in rapamycin-based anti-cancer therapies that may inevitably lead to therapeutic failure. In the current study, we evaluated treatment effects of ATP-competitive dual mTOR kinase inhibitor AZD8055 on cancer cells that have acquired resistance to rapamycin, and underpinning molecular mechanisms. To establish cells with acquired rapamycin resistance, PTEN-mt prostate cancer PC-3 cells were gradually treated with increasing concentrations of rapamycin (up to 10 μM) until the cells were completely unresponsive to rapamycin (PC-3RR). Cell proliferation was determined by MTT assay and clonogenic survival was tested by colony formation assay. m7G pull-down assay was employed to detect the cap-dependent translation. mTOR downstream pathways, including p-S6K (T389)/p-S6 (S235/236), p-4EBP1 (T37/S46) and p-Akt (S473) were detected by Western Blotting. PC-3RR cells essentially failed to respond to rapamycin, with IC50 values greater than 1 μM. However, AZD8055 suppressed PC-3RR proliferation in a dose dependent manner, with IC50 &amp;lt; 30 nM. Similarly, clonogenic capacity was impaired by AZD8055 to a greater extent than was the case for rapamycin. At the molecular level, AZD8055, but not rapamycin, strongly prevents the dissociation of 4E-BP1 from eIF4E. Further, while the p-S6K and p-S6 pathway was potently inhibited by both agents, AZD8055 displayed more striking inhibition on p-4E-BP1 and p-Akt than rapamycin. Interestingly, similar to rapamycin, AZD8055 slightly increased p-Akt (T308), suggesting the existence of the PI3K-mediated feedback loop. These findings indicate that AZD8055 significantly inhibits malignant functions in cancer cells that are highly resistant to rapamycin. Such effects are likely to be associated with the deactivation of rapamycin-insensitive mTOR downstream pathways. These data provide preliminary evidence for future evaluation of ATP-competitive mTOR inhibitors in cancer models that are resistant to rapamycin analogs. Citation Format: Yao Dai, Dietmar Siemann. mTOR kinase inhibitor AZD8055 reverses acquired rapamycin resistance in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5357.
Abstract 2228: A multi-omic perspective of how selection shapes blood cancer risk phenotypes in aging populations
Authors: Kimberly Skead, David Soave, Marie-Julie Fave, Vanessa Bruat, Quaid Morris, Philip Awadalla
Journal: Cancer Research (2022)

Abstract The genetic architecture of blood is highly complex with germline polymorphisms, somatic point mutations, and larger chromosomal alterations playing a role in shaping the fitness of the immune cells. Many advances have been made in understanding how the age associated acquisition of point mutations and somatic structural variants (SSVs) in blood, termed Age-Related Clonal Hematopoiesis (ARCH), predispose individuals to hematological cancer or cardiovascular disease. Yet, ARCH is commonly observed in healthy individuals and our ability to predict who is at risk of progressing to disease remains limited. A previous study which integrated deep learning and population genetics methods to evaluate the complex interplay of selection on point mutations in deeply sequenced blood samples highlighted the role that negative selection plays in prevention progression to hematological cancer. Here, we interrogate the mutational and selective pressures within blood to better understand how the full spectrum of somatic changes within an individual impact clonal fitness and disease outcomes. We evaluate how selection shapes the prevalence of large somatic structural variation in blood sampled from 15,910 individuals across over 20 different genetic ancestries, including the Thousand Genomes Study and the Canadian Partnership for Tomorrow’s Health study. Using dense genotyping arrays, we capture SSVs among 20 populations and find that ARCH attributed to somatic structural variation is three times as high as previously reported with up to 14% of individuals harbouring at least one large SSV in their blood. We estimate the rate at which SSVs accrue in blood cells and find that selection impacts the size and frequency of SSVs within individual blood populations. To determine the functional impact of clonal mutations on molecular phenotypes, we investigate the relationship between structural variation and the transcriptome. We show that gains, losses and copy number neutral variants impact gene expression distinctly, with stabilizing selection shaping the penetrance of copy number alterations in gene expression. Our work shows how different classes of selection shape clonal dynamics in blood thus enabling us to better understand why certain individuals are at a high risk of malignancy. Citation Format: Kimberly Skead, David Soave, Marie-Julie Fave, Vanessa Bruat, Quaid Morris, Philip Awadalla. A multi-omic perspective of how selection shapes blood cancer risk phenotypes in aging populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2228.
Abstract 23: Will novel systemic treatments alter the benefit of lung cancer screening?: A microsimulation study
Authors: Kemal Caglar Gogebakan, Jane Lange, Christopher Slatore, Ruth Etzioni
Journal: Cancer Research (2022)

Abstract Background: The U.S. Preventive Services Task Force has recently updated its 2013 lung cancer screening guidelines with low-dose computed tomography. In the last decade, population level mortality for advanced non-small cell lung cancer fell significantly due to the novel targeted and immunotherapy-based treatments. Moreover, with detection of new molecular targets, these therapies are expected to become the ultimate curative options. However, how these treatments might impact the benefits of lung cancer screening is unknown. Methods: We utilize a computer microsimulation modeling framework to screen the U.S. population aged 50 to 80 who had a 20 pack-year smoking history and currently smoked or had quit within the past 15 years under both standard treatments (chemotherapy and radiotherapy) and novel treatments (immunotherapy and targeted therapy) settings. The corresponding mortality reductions associated with the stage shift via low-dose computed screening are projected for each setting. Results: Over 25 years, risk-targeted screening saves 243 lives per 20,000 under standard therapies (12% mortality reduction) and 99 per 20,000 under fully adopted novel therapies (6% mortality reduction). Under standard treatment, 1.28 cancers are over-diagnosed per life saved; under fully adopted novel therapies, this increases to 3.46. Over 25 years the number needed to screen to avert one death is 82 under standard treatment and 202 under fully adopted novel therapies. Conclusions: Ongoing transition from chemotherapy and radiotherapy to novel immunotherapies and targeted therapies may reduce the expected lives saved by low-dose computed tomography screening. Screening recommendations might need to be reconsidered as novel treatments become widespread. Citation Format: Kemal Caglar Gogebakan, Jane Lange, Christopher Slatore, Ruth Etzioni. Will novel systemic treatments alter the benefit of lung cancer screening?: A microsimulation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 23.
Abstract 3266: The KDM5 inhibitor PBIT reduces proliferation of castration-resistant prostate cancers via the induction of senescence
Authors: Tunde M. Smith, Zhenbang Chen, LaMonica V. Stewart
Journal: Cancer Research (2022)

Abstract The members of the KDM5 family of lysine demethylases are best known for their ability to demethylate di- and trimethylated histone H3 at lysine 4 (H3K4me3). However, recent studies suggest at least three family members (KDM5A, KDM5B and KDM5C) promote prostate cancer growth and progression and may serve as effective therapeutic targets for this disease. Previous work from our laboratory has shown that 2-4(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT), a compound that inhibits the enzymatic activity of multiple KDM5 isoforms, reduces the viability of castration-resistant prostate cancer cells. The goal of this study was to further characterize the anti-tumor effects of PBIT within human prostate cancers. Two models of human castration-resistant prostate cancer were used to define the effects of PBIT: the androgen receptor (AR) positive C4-2B cells and the PC3 cells, which express little to no AR. Our group initially demonstrated via quantitative RT-PCR analysis that PC3 and C4-2B cells express varying amounts of KDM5A, KDM5B, and KDM5C, the therapeutic targets of PBIT. Presto Blue assays were next performed to determine the extent to which PBIT alters cell proliferation. Micromolar concentrations of PBIT significantly reduced prostate cancer cell proliferation in a time- and concentration-dependent manner. Data from Cell Death ELISAs suggest that PBIT at a concentration of 10 μM did not significantly induce apoptosis within C4-2B or PC3 cells. However, PBIT does appear to induce cellular senescence within the PC3 cell line. The level of senescence associated beta-galactosidase staining was increased in PC3 cells following treatment with 10 μM PBIT. Furthermore, PBIT increased protein levels of a second senescence marker, lamin B1. Together, these data suggest that the induction of senescence contributes to the anti-proliferative effect of PBIT. Citation Format: Tunde M. Smith, Zhenbang Chen, LaMonica V. Stewart. The KDM5 inhibitor PBIT reduces proliferation of castration-resistant prostate cancers via the induction of senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3266.
Abstract 2436: CIRBP is a functional mediator of leptomeningeal metastasis
Authors: Rima Ezzeddine, Matthew Dankner, Paul Savage, Steven Hebert, William Brothers, Matthew G. Annis, Sarah M. Maritan, Marc R. Fabian, Claudia Kleinman, Morag Park, Peter M. Siegel
Journal: Cancer Research (2022)

Abstract Background: Cold-Inducible RNA Binding Protein (CIRBP) has been implicated in cancer initiation. Moreover, we have previously identified an association of CIRBP with the invasive growth of parenchymal brain metastases. Using a patient-derived xenograft (PDX) model, in which cells implanted in the mouse mammary fat pad spontaneously metastasize to the leptomeninges, we identified CIRBP as being elevated in leptomeningeal metastases (LM) compared to matched primary mammary tumors. LM grow in the subarachnoid space that harbors the cerebral spinal fluid (CSF). The leptomeninges represent an inhospitable environment for disseminated cancer cells since the CSF is mitogen and nutrient poor. To investigate the importance of CIRBP for metastatic breast cancer cells in the leptomeninges, we stably reduced CIRBP expression in MDA-MB-231 cells and performed mammary fat pad and cranial injections. CIRBP knockdown had no influence on primary tumor growth, but diminished growth within the brain. Hypothesis: We hypothesize that CIRBP functions as a stress response protein enabling cancer cells to grow in the harsh environment of the CSF. Results: In response to various cellular stressors, such as hypothermia, hypoxia or UV irradiation, CIRBP can translocate from the nucleus to the cytoplasm. We show that culturing MDA-MB-231 cells in artificial CSF (aCSF) also causes CIRBP relocation from nucleus to cytoplasm. Using RNA-IP approaches, we have identified mRNAs bound by CIRBP in breast cancer cells treated with aCSF. Ultimately, we will determine whether any of the identified CIRBP-regulated targets contribute to the formation of LM. Finally, we have generated CIRBP variants that are confined either to the nucleus or the cytoplasm. We are currently assessing the ability of these compartment-restricted CIRBP proteins to promote the formation of central nervous system metastases. Conclusions: We have identified CIRBP as a promoter of leptomeningeal metastasis. Our results have begun to reveal the mechanisms through which CIRBP mediates this process. Citation Format: Rima Ezzeddine, Matthew Dankner, Paul Savage, Steven Hebert, William Brothers, Matthew G. Annis, Sarah M. Maritan, Marc R. Fabian, Claudia Kleinman, Morag Park, Peter M. Siegel. CIRBP is a functional mediator of leptomeningeal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2436.
Bronchoalveolar lavage (BAL) amylase and pepsin levels as potential biomarkers of aspiration pneumonia
Authors: T. Suzuki, M. Saitou, Y. Utano, K. Utano, K. Niitsuma
Journal: Pulmonology (2022)

There are currently no established markers for aspiration pneumonia. We hypothesized that bronchoalveolar lavage (BAL) amylase and pepsin might be candidate biomarkers for aspiration pneumonia.This cross-sectional study reviewed consenting adults who underwent clinically-indicated bronchoscopy at Aizu Medical Center. BAL samples were obtained using standardized methods. Amylase levels were measured in our clinical laboratory, and pepsin levels were assessed by ELISA.Aspiration pneumonia was clinically diagnosed based on the guidelines of the Japanese Respiratory Society in 48 of the 327 participants. Median BAL salivary amylase and pepsin levels in this group were 702.0 U/L and 12.7 ng/ml respectively, which were significantly higher than in non-aspiration pneumonia patients. BAL amylase ≥204 U/L had 77.1% sensitivity and 84.2% specificity as a diagnostic index, and the area under the receiver operating characteristic (ROC) curve was 0.859 (95% confidence interval (CI), 0.803-0.915). Similarly, BAL pepsin levels of ≥7.45 ng/ml had 87.2% sensitivity and 59.9% specificity for identifying aspiration, and the area under the ROC curve was 0.757 (95% CI, 0.688-0.826). Multivariate regression demonstrated that BAL amylase ≥204 U/L and BAL pepsin ≥7.45 ng/ml were associated with significantly higher odds for aspiration pneumonia (odds ratio (OR) 10.0, 95% CI, 4.51-22.2, and OR 8.81 95% CI, 3.32-23.4, respectively). There were no significant associations between risk factors for aspiration pneumonia and BAL amylase and pepsin levels.BAL amylase and pepsin might be useful biomarkers for suggesting aspiration pneumonia, and could be objective markers without relying on known risk factors for aspiration.
Abstract CT224: Multi-institutional randomized phase-3 trial comparing cancer stem cell-targeted vs physician-choice treatments in patients with recurrent high-grade gliomas (NCT03632135)
Authors: Tulika Ranjan, Soma Sengupta, Alexander Yu, Candace M. Howard, Ricky Chen, Rekha Chaudhary, Nicholas Marko, Dawit Aregawi, Michael Glantz, Jon Glass, Richard M. Green, Christine Lu-Emerson, Aaron Mammoser, Hugh Moulding, Steven Jubelirer, Jason Schroeder, Mark Anderson, Frances Chow, Seth Lirette, Krista Denning, Anthony Alberico, Jagan Valluri, Pier Paolo Claudio
Journal: Cancer Research (2022)

Abstract Background: Clinical outcomes in patients with recurrent high-grade glioma (HGG) remain poor. Cancer stem cells (CSCs) have been implicated in metastasis, treatment resistance and recurrence of HHGs. We have shown in several clinical studies that anti-CSC-directed therapy provides benefits in many cancer types; however, this is the first report of a randomized clinical trial evaluating it for recurrent HGGs. Objective: Determine whether CSC-targeted cytotoxic agents selected by ChemoID assay-guided therapy improves survival in patients with recurrent HGG. Design, Settings, and Participants: In this parallel-group, randomized, phase-3 clinical trial, patients at 13 clinical sites in the USA with grade-III/IV recurrent glioma (2016 WHO guidelines) were randomized 1:1 to either ChemoID assay-guided therapy or physician-choice therapy, and then treated and followed until unacceptable toxic effects, hospice, or death. Main Outcomes and Measures: The primary endpoint was overall survival (OS). Results: Combined median follow-up was 9 months. Median OS (mOS) was 12.5 months (95% CI, 10.2-14.7) in the ChemoID assay-guided group vs 9 months (95% CI, 4.2-13.8) in the physician-choice group (log-rank P = .010). Risk of death was significantly lower in the ChemoID assay group (HR = 0.44; 95% CI, 0.24-0.81; P = .008). Median progression free survival (PFS) was 10.1 vs 3.5 months (95% CI, 4.8-15.4 vs 1.9-5.1) (HR, 0.25; 95% CI, 0.14-0.44; P &amp;lt; .001). Conclusions and Relevance: Primary endpoint was met in this randomized clinical trial. The mOS was 3.5 months longer in the ChemoID assay-guided group vs the physician-choice group demonstrating the clinical advantage of treating HGG patients using CSC personalized therapy. Citation Format: Tulika Ranjan, Soma Sengupta, Alexander Yu, Candace M. Howard, Ricky Chen, Rekha Chaudhary, Nicholas Marko, Dawit Aregawi, Michael Glantz, Jon Glass, Richard M. Green, Christine Lu-Emerson, Aaron Mammoser, Hugh Moulding, Steven Jubelirer, Jason Schroeder, Mark Anderson, Frances Chow, Seth Lirette, Krista Denning, Anthony Alberico, Jagan Valluri, Pier Paolo Claudio. Multi-institutional randomized phase-3 trial comparing cancer stem cell-targeted vs physician-choice treatments in patients with recurrent high-grade gliomas (NCT03632135) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT224.
Abstract 2438: Determining the role of non-mutated C-Raf kinase in metastatic disease
Authors: Lisa H. Ta, Janai R. Carr-Ascher, Weixian Deng, Brandon L. Tsai, Wendy Tran, Donny Gun, Donghui Cheng, Jihui Sha, Yeonjoo Hwang, John W. Phillips, Matthew B. Obusan, Nathanael J. Bangayan, Miyako Noguchi, Zhiyuan Mao, Chia-Chun Chen, Liang Wang, Grigor Varuzhanyan, John D. Gordon, James W. Wohlschlegel, Owen N. Witte
Journal: Cancer Research (2022)

Abstract Many aggressive epithelial cancers do not carry targetable driver mutations (Mendiratta et al. 2021, NCI-MATCH Clinical trial NCT02465060). Commonly altered signaling pathways highlight the propensity for tumors to depend on such pathways for growth and survival where genomic alterations may not be required for pathway activation. The Raf family kinases are crucial mediators of the Ras/Raf/MEK/ERK (MAPK) cascade, which has been shown to be upregulated in a subset of metastatic cancers and are mutated in many epithelial cancers. A recent study suggests non-mutated C-Raf can drive metastasis to the lungs, bone, and various other tissues (Faltermeir et al. 2016). Though the mechanism of C-Raf driven metastasis is likely through MAPK activation, C-Raf has been demonstrated to possess MAPK independent roles that may also contribute to this phenotype. In this study, we explored various C-Raf functions as drivers of metastasis in an intracardiac mouse model system. Using a series of Raf knock-out cell lines and mutants targeting functional residues in C-Raf, we demonstrated that C-Raf dimerization is necessary to drive metastasis. We further showed that the metastasis-promoting activity of C-Raf is dependent on co-expression of its family member, B-Raf, for an accelerated metastatic phenotype. However, overexpression of a kinase-dead C-Raf mutant was still able to produce metastases albeit with lower efficiency, suggesting C-Raf possesses non-kinase dependent functions that also contributed to metastasis. Together, these results point to the importance of Raf non-canonical roles in oncogenic processes that may be unappreciated in metastatic disease. Citation Format: Lisa H. Ta, Janai R. Carr-Ascher, Weixian Deng, Brandon L. Tsai, Wendy Tran, Donny Gun, Donghui Cheng, Jihui Sha, Yeonjoo Hwang, John W. Phillips, Matthew B. Obusan, Nathanael J. Bangayan, Miyako Noguchi, Zhiyuan Mao, Chia-Chun Chen, Liang Wang, Grigor Varuzhanyan, John D. Gordon, James W. Wohlschlegel, Owen N. Witte. Determining the role of non-mutated C-Raf kinase in metastatic disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2438.
Abstract 13: Novel CRISPR screening approach identifies regulators of cell-free DNA release in vitro
Authors: Brad A. Davidson, Adam X. Miranda, Sarah Croessmann, Ben Ho Park
Journal: Cancer Research (2022)

Abstract Despite the well-documented benefits of circulating tumor DNA (ctDNA) based liquid biopsy, including screening, prognostication, and treatment monitoring, there remain several concerns with its application. Chief among these concerns are imperfect sensitivity and specificity, particularly pre-diagnosis and after tumor resection, when ctDNA burden is low. Cell death, either through apoptosis or necrosis, has been the most widely accepted mechanism of DNA release. Recent studies have also suggested active release through extracellular vesicles as a paradigm for DNA release. However, this pathway remains highly debated in terms of its contribution, mechanism, and even credibility. To address the deficiencies in ctDNA detection in the clinic and the lack of basic mechanistic knowledge of cf/ctDNA release, we performed an in vitro CRISPR screen on MCF10A cells to identify regulators of DNA release. This normal breast epithelial cell line was chosen because MCF10A cells release DNA into cell culture media with a similar fragmentation pattern to that observed in human blood. After lentiviral infection with the genome-wide Brunello CRISPR-Cas9 knockout library, the population of knockouts identified in the genomic DNA of cells attached to the plates was compared to the population of knockouts found in the DNA released into the cell-depleted culture media. Genes with skewed representation were considered potential regulators of DNA release. Our analysis identified several genes in the TRAIL apoptotic pathway including FADD, as well as several genes encoding RNA-binding proteins including Sam68. Knockout of Sam68 and FADD in MCF10As, MDA-MB-468 breast cancer cells, and NCI-H841 lung cancer cells lead to decreases in DNA release. Previous studies have hypothesized that the fragment size of released DNA is dependent on release mechanism. However, the decreases observed in our knockout cell lines were not limited to a specific fragment size of DNA. Application of the small molecule apoptosis inhibitor Z-VAD-FMK also recapitulated the DNA release phenotype seen in our knockout cell lines. From these results, we conclude that apoptosis is the major source of DNA release from cancer cells, and that fragment size is not the indicator of release mechanism it has been presumed to be. Mechanistic studies of DNA release such as this could lead to the ability to modify the amount of ctDNA in circulation, which would significantly improve accurate detection in the clinic. Citation Format: Brad A. Davidson, Adam X. Miranda, Sarah Croessmann, Ben Ho Park. Novel CRISPR screening approach identifies regulators of cell-free DNA release in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 13.